Our Take
One win out of two endpoints is not a win: Epkinly delayed lymphoma relapse but did not extend life, and the post-hoc adjustments that might explain why (pandemic deaths, unequal follow-on therapy) will not move regulatory needles the way primary data does.
Why it matters
The FDA's August 2025 guidance now treats overall survival as both efficacy and safety measure, raising the bar for single-agent approvals in blood cancers. Genmab faces the same headwind that led to Roche's Columvi rejection in 2025, making second-line monotherapy adoption unlikely without OS parity.
Do this week
Oncology Medical Directors: audit your R/R LBCL treatment algorithms now to confirm whether Epkinly monotherapy remains an option pending regulatory clarity, since the chemotherapy backbone will likely persist as standard of care.
PFS gain but no survival signal in 483-patient trial
Genmab and AbbVie presented Phase III results for Epkinly (epcoritamab), a subcutaneous CD3×CD20 bispecific antibody, in patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) who were ineligible for or had relapsed after autologous stem-cell transplant. The EPCORE DLBCL-1 trial enrolled 483 patients with one or more prior therapies, representing a population with poor outcomes.
Epkinly met the progression-free survival (PFS) primary endpoint with a hazard ratio of 0.74 (95% CI 0.60–0.92; p=0.0059) and a 24-month PFS of 30% versus 13% for investigator's choice chemotherapy. The drug also delivered a 38% complete response rate versus 26% for chemotherapy, a longer duration of complete response (not reached versus 10.8 months), and delayed time to next treatment (6.6 versus 4.3 months).
However, overall survival was not significantly different between arms (HR 0.96; 95% CI 0.77–1.20), failing the second primary endpoint. With median follow-up of 43.2 months in the Epkinly arm and 42.3 months in the control arm (per the trial), the investigators attributed the OS miss to two confounders: Covid-19 deaths accounted for 9% of the experimental arm versus 3% of controls, and the chemotherapy arm received more effective post-progression therapies (31% versus 6%). A post-hoc analysis adjusting for both moved the OS hazard ratio to 0.76 (95% CI 0.59–0.99), favouring Epkinly, but this adjustment was not part of the prespecified analysis.
Safety data showed higher rates of grade 3–4 infections in the Epkinly arm (30% versus 12%), attributed to longer mean exposure (11 months versus 2 months) and pandemic effects. On an exposure-adjusted basis, the rates were comparable (4.3 versus 4.9 per 100 patient-months, per the trial summary). Grade 5 events occurred in 17% of the experimental arm versus 6% of controls, again driven by longer exposure and pandemic deaths.
Regulatory path now uncertain under tightened FDA OS standards
This is the first Phase III trial of a CD3×CD20 bispecific monotherapy to beat chemotherapy on PFS in this population, a category-first result. Yet the failure to meet OS as a primary endpoint creates a regulatory aperture. The FDA's August 2025 draft guidance on assessing OS treats OS as both efficacy and safety measure, explicitly using it to flag therapies that improve response while adding toxicity. That lens makes post-hoc OS adjustments less persuasive in an approvability conversation.
Precedent is unfavourable. In 2025, the FDA rejected Roche's Columvi (glofitamab), also a CD3×CD20 bispecific and Epkinly's direct comparator, in second-line ASCT-ineligible R/R LBCL patients, citing insufficient US patient enrollment (9% versus 48% in Asia). EPCORE DLBCL-1 recruited more than 50% of patients in North America and Western Europe, so recruitment geography is not a barrier. However, the Columvi precedent signals that the agency is calibrating risk-benefit narrowly in this class and indication. Genmab will seek guidance from global regulators, but US approval for monotherapy in second-line remains contested.
Epkinly does have a commercial lifeline: its combination with gemcitabine and oxaliplatin is already listed as an NCCN-preferred regimen for CAR T-ineligible R/R DLBCL, despite lacking formal FDA approval for that combination. The drug is also under evaluation in other haematological malignancies, with analyst consensus forecasting global sales of $2.795 billion by 2032 (per GlobalData), suggesting investors expect eventual approval in a broader portfolio.
OS data will drive treatment guidelines, not PFS alone
For oncology teams evaluating Epkinly for second-line use, the PFS benefit is real but insufficient to shift standard-of-care algorithms in the absence of OS benefit. Chemotherapy backbones will persist as the regulatory reference and clinical default unless Genmab secures approval via an alternative pathway (combination therapy, earlier-line indication, or a different regulatory framework). Do not assume that a meeting with regulators will yield fast clarity; the FDA's tighter OS stance creates headwind.
The trial enrolled a deeply pretreated population with one or more prior therapies, representing genuine unmet need, but also a population that will face survival scrutiny rather than response-rate credit. Plan second-line therapy discussions around chemotherapy options and CAR T candidacy until regulatory status clarifies.